The metabolic responses to injury, infection and inflammatory diseases are composed of a variety of physiologic changes which are thought to limit the extent and magnitude of the injury or infection and promote wound healing. J. J. Pomposelli et al., J. of Parenteral and Enteral Nutrition, 12(2):212-218 (1988). The metabolic responses are characterized by a generalized and stereotypical pattern of reactions with limited specificity related to the etiology of the initiating event or to the organism. The physiologic changes observed during this response include an increased mobilization of amino acids from peripheral tissues, with a subsequent increase in the synthesis of hepatic proteins, a prominent leukocytosis with neutrophilia in the blood, as well as a redistribution in plasma trace metals. Some endocrinologic changes include a rise in plasma insulin, glucagon, and glucocorticoids. Fever, and a negative nitrogen balance are also indicative of the metabolic response to injury and infection. J. J. Pomposelli et al., J. of Parenteral and Enteral Nutrition, 12(2):212-218 (1988).
The metabolic response is orchestrated by cell mediators. A few of these cell mediators include interleukin-1 alpha and beta (IL-1), tumor necrosis factor alpha/cachetin (TNF), tumor necrosis factor beta/lymphotoxin, colony stimulating factor (CSF), platelet-derived growth factor (PDGF) and gamma interferon. These mediators, or monokines, are secreted by cells known as mononuclear phagocytes, in response to injury or infection of the host.
The primary immunologic mediator involved in the cellular defense mechanism is the lymphokine interleukin-1 (IL-1), which is synthesized by mononuclear phagocytes. Numerous studies have been carried out on the application of IL-1 to enhance non-specific resistance to infection in a variety of clinical states. Pomposelli et al., J. Parent. Ent. Nutr.,12(2):212-218, (1988). The major problem associated with the use of IL-1 and other cellular mediators in humans is toxicity and side effects resulting from the disruption of the gentle balance of the immuno-regulatory network. Fauci et al., Anals. of Internal Medicine, 106:421-433 (1987). Therefore, it may be more reasonable, physiologic and effective to mimic the endogenous response of monokines by stimulation of their release rather than their exogenous administration.
Immunocompromised individuals e.g., chemotherapy or radiation therapy patients, patients having a immuno-depressing disease or disorder such as AIDS, or the over-65 age group, comprise a large group of patients who are at a high risk of post-operative or other complications. These complications are mainly due to secondary infections resulting from the treatment or surgical procedure and have severe implications in terms of patient morbidity and mortality.
Protein malnourished, injured and immunocompromised individuals have a substantially diminished capacity to produce the necessary metabolic responses to infection or injury which, in well nourished or immune-normal patients, enhance the body's ability to assemble humoral and cellular defense mechanisms involving leukocytes. In fact, protein malnutrition has been directly associated to an increased occurence and severity of bacterial infections. Moldawer et al., J. Theor. Biol., 106:119-133 (1984).
Recent interest has focused on the treatment or prevention of disease by stimulating the production of immunologic cell mediators with microbial or plant-derived substances. For example, yeast cell wall glucans have an ability to stimulate certain aspects of the immune sysetm in mammals. The mechanism for this effect has been characterized, and involves a specific glucan receptor which is present on peripheral blood leukocytes and extravascular macrophages. Czop, J. K., Path. Immunopath. Res., 5:286-296, (1986). Activation of this receptor with glucans stimulates the amplification of host defenses which involves a cascade of interactions primarily mediated by macrophages and macrophage-derived products, thereby increasing a patient's resistance to infection.
The cell walls of yeast organisms are mainly composed of .beta.-linked glucan, a polysaccaride comprised of a backbone chain of .beta.(1-3) glucose units with a low degree of inter- and intra- molecular branching through .beta.(1-6) linkages. A minor component that consists mainly of highly branched .beta.(1-6) glucan is closely associated with the main component, and both together comprise the alkali-insoluble glucan fraction.
The structure and/or preparation of .beta.-glucans has been described by Manners et al., Biochem J., 135:31-36 (1973), Sietsma et al., J. of General Microbiology, 114:99-108 (1979), Kopecka et al., J. of Cell Biology, 62:66-76 (1974), Kreger et al., J. of General Microbiology, 92:202-220 (1975) and DiLuzio et al. Int. J. of Cancer, 24:773-779 (1979). Use of a phosphorylated glucan for therapeutic purposes has been described by DiLuzio in U.S. Pat. No. 4,739,046 and by Williams et al. in U.S. Pat. No. 4,761,402.